Heterosis is commonly observed in hybrid individuals exhibiting vigor greater either parent. Interactions between the effects of heterosis and polyploidy have been described and indicate that heterosis is stronger in polyploid individuals. However, neither the molecular basis of heterosis in diploids nor the mechanisms leading to the observed interaction with ploidy level are understood at the moment. Several genetic models exist which suggest that heterosis is due to either dominance complementation of deleterious recessives or allelic interactions and overdominance. However, these models have remained unchanged for almost a century, and the available data cannot distinguish them clearly. Tools are now available to investigate heterosis and polyploidy effects on genome-wide expression levels, to test the genetic models, and to formulate a model for the underlying molecular mechanisms. Focusing mainly on the use of microarrays and gene expression analysis in Zea mays, the proposed experiments will allow us collect the necessary data to develop a molecular model for heterosis. The results will be of great significance for agriculture because of the impact of heterosis on yield, and also forevolutionary biology as polyploidy and heterosis are important factors in the evolutionary history of many species.